James G. Krueger, MD, PhD: ‘Over the past few years, there has been a very clear identification of comorbidities associated with the disease that drive earlier death.’

Over the past 20 years, knowledge of the causes of psoriasis has evolved from the general description of T cells to identifying a specific T-cell subset that affects the IL-23/Th-17 pathway that drives the disease. The result is the development of biologic drugs that promise to completely suppress the disease, and a hope that tolerance could be established in patients.

“These new drugs have shown superior activity in getting to PASI 90 and PASI 100. The PASI 100 result is that the skin is completely clear, so the disease is effectively eliminated or completely suppressed. It is not cured because if these drugs are stopped, psoriasis does come back,” said James G. Krueger, MD, PhD.

Dr. Krueger discussed these advances during Sunday’s Eugene J. Van Scott Award for Innovative Therapy of the Skin and Phillip Frost Leadership Lecture, “The Translational Revolution for Treatment of Psoriasis with Targeted Therapeutics,” and in a separate interview. He is director of the Milstein Medical Research Program and the D. Martin Carter professor in the clinical investigation laboratory of investigative dermatology at Rockefeller University, New York.

Modern psoriasis research started with the study of diseased skin tissue that eventually led researchers to show that the disease was caused by T cells. This led to the development of T cell-targeted therapeutics, such as efalizumab.

“The evolving dissection of the disease then involved trying to look at different T-cell subsets and associated cytokines as fundamental causes of the disease,” Dr. Krueger said. “We worked our way through different immune pathways and hypotheses in large part aided by the availability of specific biologic therapeutics that could be given to people with the disease.

“It’s really a combination of laboratory work that has demonstrated specific pathways that are activated in conjunction with mechanistic trials with these targeted therapeutics that have let us decipher what is actually causing psoriasis. In the end, what is actually causing psoriasis is a central pathway, the IL-23/Th-17 pathway.”

Armed with these findings, six biologic drugs to control psoriasis have been developed. One, the anti-IL-17 drug secukinumab, was approved by the FDA in January. Five other drugs are in phase II trials and target either IL-23 or IL-17, Dr. Krueger said.

Meanwhile, the most effective psoriasis drug in use is ustekinumab, which has a PASI 75 response in 70-80 percent of patients. A PASI 75 score is defined as a 75-percent improvement in the psoriasis severity index. The new biologics have led to patients having PASI scores of 90-100 in trials.

Despite that advance, patients must continually use the drugs to control their psoriasis, but one IL-23 antibody may set a new standard.

“In the first proof-of-concept study, patients were given a single dose of this antibody, and some stayed clear for more than a year without a return of disease,” Dr. Krueger said. “That is a very impressive result in targeting what we now think is the central pathway.

“If you look at other autoimmune diseases, I think the case could be made that psoriasis is the best and most effectively treated among all human autoimmune diseases that are common and mediated by T cells.”

The next goals are to lower the cost of treatment by effectively inhibiting the IL-23/Th-17 pathway by developing better small-molecule drugs or finding a way to reregulate the immune system toward tolerance.

“If one could do this, it might have the safest and best long-term outcome for the treatment of psoriasis. You would not need to use continuous immunosuppressant drugs,” Dr. Krueger said, adding that he is the protocol chair for the Immune Tolerance Network, a multicenter study trying to develop a strategy to build tolerance.”

Another finding of this psoriasis research is that it could do more than offer relief to patients — it could extend their lives.

“Over the past few years, there has been a very clear identification of comorbidities associated with the disease that drive earlier death,” Dr. Krueger said. “There are cardiovascular diseases, kidney diseases, and a high prevalence of psoriatic arthritis. The sum of this leads to death a few years earlier than might be expected.

“One needs to establish whether we also are going to be able to impact overall health and treat some of these comorbidities that have the same fundamental immune and inflammatory activation cascade that drives skin disease. Of course, those cascades would be of the organs and tissues that set up the comorbid conditions. This has evolved to considering the whole health of psoriasis patients.”

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